: Hudson River (NY) tomcod are a feral fish population with a very high incidence (90 percent) of naturally occurring hepatocellular carcinoma. The applicant has been studying the molecular biology of Hudson River tomcod carcinogenesis, and has found frequent activation of the K-ras oncogene in these tumors. In this application, the applicant proposes to extend his studies using this valuable model system to investigate several critical issues related to environmentally induced cancer in fish. He will perform experiments to define the life stage at exposure most relevant to cancer risk in these organisms. Using modern methods of amplification of specific gene sequences (PCR) he will determine whether oncogene activation can be detected in museum specimens dating back to the early part of the century. These studies should help to clarify the role of recent environmental degradation of the Hudson River in the tomcod cancer rate. He will pursue his preliminary findings that suggest that tomcod living in the Hudson exhibit a high level of cytochrome P450 gene expression, and will investigate the possible role of this phenomenon in contributing to the carcinogenic response. Finally, he will develop cell lines from fish tumors and normal tissue isolated from Hudson River tomcod and from Maine tomcod, which show a low cancer incidence. The studies described here will shed further light on the etiology of tomcod carcinogenesis and further develop a useful model for carcinogenesis in natural out-bred populations. He also expects this research to provide data that can be used to develop new molecular biomarkers for environmental degradation and recovery.